Thierry FACON

Lille University Hospital, Lille, France

On behalf of IFM

Strategies for front-line treatment of Strategies for front-line treatment of Multiple MyelomaMultiple Myeloma

1962 1983 1986 1996 1999 2000+

BisphosphonatesBisphosphonates

Oral melphalan and prednisone

Oral melphalan and prednisone

VADVAD

High-dose dexamethasone

High-dose dexamethasone

High-dose therapy with autologous stem cell

support

High-dose therapy with autologous stem cell

support

Proteasome inhibitors

(Bortezomib)Other immuno-

modulatory agents(Lenalidomide)

Proteasome inhibitors

(Bortezomib)Other immuno-

modulatory agents(Lenalidomide)

Historical Perspective of Multiple MyelomaHistorical Perspective of Multiple Myeloma

High-dose melphalan

1984

Thalidomide

ABMTABMT

Period estimates of 10-year survival of patients with Period estimates of 10-year survival of patients with MM by major age groups in defined calendar periods MM by major age groups in defined calendar periods

from 1984-1986 to 2002-2004from 1984-1986 to 2002-2004

Brenner et al; Blood 2008; 111:2521-26

Front-line treatment in multiple myeloma Front-line treatment in multiple myeloma patients not eligible for stem cell patients not eligible for stem cell

transplantationtransplantation

Age- and Sex- Incidence Rates per 100 000/year for MM in the South Thames Area (1999-

2000)

Phekoo et al; BJH 2004; 127: 299-304

16-24 25-34 35-44 45-54 55-64 65-74 75-84 85+

60.00

50.00

40.00

30.00

20.00

10.00

0.00

Rat

e pe

r 100

,000

Age (years)

MalesFemalesFemales and Males combined

0.0

0.2

0.4

0.6

0.8

1.0

surv

ival pro

port

ion

814 621 480 289 143trt = MPT868 654 465 265 122trt = MP

Number at risk

0 12 24 36 48months

trt = MP

trt = MPT

Overall survival - All

Median 32.7 months (30.5-36.6)

Median 39.3 months(35.6-44.6)

HR=0.83 in favour of MPT, P=.005Cox model for treatment, with analysis sratified by study using a random effects (frailty) model

MRC Myeloma IX non intensive pathwayMRC Myeloma IX non intensive pathwayOlder less fit patients (approximately > 65 y)Older less fit patients (approximately > 65 y)

Morgan et al. Blood 2007; 110:1051a(abs 3593)

Morgan et al. Blood 2008; 112:245 (abs 656)

VISTA: VELCADE as Initial Standard Therapy in multiple VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with MPmyeloma: Assessment with MP

• Randomized, international, phase III trial of VMP vs MP in 682 previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions

• Stratification: β2-microglobulin, albumin, region

VMPCycles 1–4Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

Cycles 5–9Bortezomib 1.3 mg/m2 IV: d 1,8,22,29Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

MPCycles 1–9 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

RANDOMIZE

9 x 6-week cycles (54 weeks) in both arms

• Primary end point: TTP

• Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)

San Miguel et al. N Engl J Med 2008;359:906–17

VISTA:Efficacy dataVISTA:Efficacy data

ORR: VMP 71%, MP 35% CR: VMP 30%, MP 4%

Time to progression Overall survival

Pat

ient

s w

ithou

t ev

ent

(%)

VMP: 24.0 monthsMP: 16.6 monthsP < .000001

0

20

40

60

80

100VMPMP

Time (months)

• Only 5% “true” non-responders• 43% of MP patients received bortezomib upon progression• 3-y OS VMP 68.5% vs MP 54%, median OS VMP not reached vs MP 43.1 mo.

after a median FU 36.7 mo. Mateos et al.JCO,2010;28:2259-2266

Median follow-up: 25.9 months3-year OS: VMP: 72% MP: 59%P = .0032

VMPMP

Time (months)0 3 6 9 12 15 18 21 24 27

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40

MPV, an evolving standard of careFrom twice weekly to once weekly regimens

Spanish MPV; Mateos et al.Lancet Oncology 2010 Epub August 24.

Induction 6 cycles; one 6-week cycle, bortezomib 2x weekly, five 5-week cycles, bortezomib 1x weekly. Maintenance VT or VP

Italian MPV; Palumbo et al.JCO 2010 Epub October 12.Bringhen et al.Blood 2010 Epub August 31.

Induction Nine 5-week cycles, bortezomib 1x weekly.No maintenance in MPV but VT maintenance in VMPT

One-weekly schedule reduces the incidence of PN and decreases the rate of discontinuation without any reduction in efficacy

Randomized, placebo-controlled, double-blind trial in 51 centres in Europe, Australia, and Israel (N = 450)

Primary end-point: PFS

Secondary end-points: OS, TTP, ORR, TTR, duration of response, and quality of life

All patients receive VTE prophylaxis with aspirin (75–100 mg/day)

Up to 9 courses in the absence of disease progression or unacceptable adverse events; treatment in 28-day cycles

Trial NCT00405756. Available from: www.clinicaltrials.gov.

Patientswith newly diagnosed,untreated

MM who arenot eligible for a

transplant

Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21

Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21

Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Placebo days 1–21

Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Placebo days 1–21

LenalidomideLenalidomide

PlaceboPlaceboMelphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21

Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21

PlaceboPlacebo

MM-015: phase III trial of MPR vs MP for long-term control in newly diagnosed MM

RANDOMIZATION

0 5 10 15 20 25 30 35 400

25

50

75

100

Time (months)

Pat

ient

s (%

)

Progression-Free SurvivalAll Patients

HR 0.423 Log rank P < .001

HR 0.850Log rank P = .307

No. at Risk

MPR-R 152 115 89 66 35 17 2 – –MPR 153 120 90 36 17 7 – – –MP 154 112 85 43 19 2 – – –

2-Year PFS Median PFS

MPR-R 55% Not reached

MPR 24% 14.1 months

MP 16% 13.0 months

0 5 10 15 20 25 30 35 400

25

50

75

100

Time (months)

Pat

ient

s (%

)

Progression-Free Survival 65 - 75 Years of Age

HR 0.315 Log rank P < .001

HR 0.675Log rank P = .031

No. at Risk

MPR-R 116 91 75 57 31 15 2 – –MPR 116 97 77 31 16 7 – – –MP 116 82 62 29 13 1 – – –

2-Year PFS Median PFS

MPR-R 61% Not reached

MPR 27% 14.7 months

MP 10% 12.4 months

Treatment – Initial 9 cyclesTreatment – Initial 9 cycles

MPRa MP

Discontinuation rateb, %

65 - 75 years of age 17 10

> 75 years of age 34 16

Cumulative dose intensityc, %

65 - 75 years of age 88 97

> 75 years of age 56 97

a MPR includes MPR-R and MPR for the initial 9 cycles.b Discontinuation due to AEs or withdrawal of consentc Cumulative dose intensity of melphalan and lenalidomide/placebo

Len. + high-dose Dexx 4 cycles (cycle length : 28 d)

Rev. 25 mg/d, days 1-21 Dex. 40 mg/d, days 1-4, 9-12, 17-20

Len. + low-dose Dexx 4 cycles

Rev. 25 mg/d, days 1-21 Dex. 40 mg/d, days 1, 8, 15, 22

ECOG E4A03 Trial DesignECOG E4A03 Trial Design

Newly diagnosedMM patients

(n = 445)

Primary objective:response rate and toxicity

Len + high-dose Dex vs Len + low-dose DexLen + high-dose Dex vs Len + low-dose Dexin newly diagnosed patients with myelomain newly diagnosed patients with myeloma

Rajkumar et al. Lancet Oncology 2010;11:29-37

ECOG/E4A03 Adverse eventsECOG/E4A03 Adverse events

Type (≥ Grade3) RD

(N=223)Rd

(N=220)P

DVT/PE 26 % 12 % 0.0003

Infection/Pneumonia 16 % 9 % 0.04

Cardiac ischemia 3 % 0.5 % 0.07

Any non Hem toxicity (Grade ≥ 3)

65 % 48 % 0.0002

Toxicity of any type (Grade ≥ 4)

21 % 14 % 0.0002

Early deaths (< 4 mo. All pts) 5 % 0.5 % 0.003

Rajkumar et al. Lancet Oncology 2010;11:29-37

FIRST: Lenalidomide + LD-dex vs. MPT(IFM 07-01)

RR

LD (28-day cycle)

Oral dexamethasone on day 1, 8, 15, 22

Oral lenalidomide once daily on days 1-21

LD (28-day cycle; up to 18 cycles)

Oral dexamethasone on day 1, 8, 15, 22

Oral lenalidomide once daily on days 1-21

MPT (6-wk cycle; up to 12 cycles)

Oral melphalan and prednisone on days 1-4

Oral thalidomide once daily on days 1-42

MMTreatment until

progressive disease (PD)

• Pts: Previously untreated MM pts >65 yrs old or not a candidate for ASCT

• Primary Endpoint: Progression-free survival (PFS)

Treatment selection: elderly patients

Treatment should be selected based on:

Biological age, comorbidities, overall clinical impression

Dose adjustments:

Standard schedules for fit patients requiring quick relief from symptoms

Less intense treatment approach for frail patients and those with comorbidities (heart, lung, kidney, liver, diabetes) or aged >75 years

Need to do what is best for an average elderly MM patient

Newly diagnosed frail elderly patients with MMNewly diagnosed frail elderly patients with MM

Symptomatic treatments remain essential

Highest doses of drugs are not optimal

Dexamethasone

MP+ studies

Avoid excessive toxicity

careful treatment monitoring

dose reduction guidelines

particularly in early stages of treatment

Need to consider Quality of life as factor

New options for patients eligible for New options for patients eligible for

transplantationtransplantation

Induction regimens in the era of novel agentsInduction regimens in the era of novel agents

IFM 2005/01 GIMEMA HOVON-GMMG PETHEMA/GEM

Harousseau

VD vs VAD

(n=197 vs 184) (ASH

2008, joint

ASH/ASCO

symposium)

Cavo

VTD vs TD

(n=226 vs 234)

(IMW 2009;

Abstract 451)

Sonneveld

PAD vs VAD

(n=150 vs 150)

(IMW 2009;

Abstract 152)

Rosinol

VTD vs VBCMP/VBAD+V vs TD

(n=61 vs 58 vs 61)

(IMW 2009; Abstract 160)

Results post-ASCT

CR 18% vs 10%* 41% vs 20%* 15% vs 4%* 48% vs 43% vs 23%

CR + nCR 40% vs 22%* 54% vs 29%* n/a n/a

≥VGPR 61% vs 44%* 75% vs 53%* 59% vs 47% n/a

CR + PR 91% vs 91% n/a 92% vs 77%* 77% vs 70% vs 62%

Summary of post-transplant results in Phase III Summary of post-transplant results in Phase III bortezomib trialsbortezomib trials

Bortezomib induction regimen results in high CR/nCR and VGPR rates post-transplant

*significantly different

n/a: not available

Phase III VD vs vTD as induction prior to ASCTPhase III VD vs vTD as induction prior to ASCTIFM 2007/02IFM 2007/02

Harousseau et al. ASH 2009 (Abstract 354)

RANDOMIZE

Bortezomib 1.3 mg/m2 d1, 4, 8, 11Dex 40 mg d1–4 and 8–11 (c3+4 only)

Bortezomib 1.0 mg/m2 d1,4,8,11Thal 100 mg dailyDex 40 mg d 1–4 and 8–11 (c3+4 only)

VD

vTD

4 x 21-day cycles

Patients with <PR after cycle 2 could have bortezomib increased to 1.3 mg/m2 and thal increased to 200 mg in the absence of PN

Stratified by β2M and del(13) by FISH

Primary Objective: Induction CR rate

Secondary Objectives: ≥VGPR, ≥PR, toxicity (including PN)

FISH, fluorescent in situ hybridization

IFM 2007/02: VD vs vTD as induction IFM 2007/02: VD vs vTD as induction treatment prior to ASCT treatment prior to ASCT

Harousseau et al. ASH 2009, abs 354Harousseau et al. ASH 2009, abs 354

• 205 patients from Mar. 2008 to Jan. 2009 (191 pts evaluable)

vTD should be considered as a new standard for induction treatment prior to ASCT

Response (%)

VD vTD

CR 12 14

VGPR* 36 50

PR 81 91

*P=0.047

Toxicity (%)

VD vTD

Treatment reduction

17 7

PN gr 2* 28 14

PN gr 3 6 2

*P=0.02

Phase I/II: bortezomib, lenalidomide, dex (VRD) Phase I/II: bortezomib, lenalidomide, dex (VRD) in newly diagnosed MMin newly diagnosed MM

CR/nCR (%) ≥VGPR (%) ≥PR (%)

All patients (n=66)

Response at cycle 4 6 11 74

Response at cycle 8 23 53 95

Best response 39 67 100

• TreatmentTreatment– Up to 8 3-week cycles: Bortezomib 1.0/1.3 mg/mUp to 8 3-week cycles: Bortezomib 1.0/1.3 mg/m22, Len 15–25 mg, Dex 40/20 mg , Len 15–25 mg, Dex 40/20 mg

• ResultsResults

• Median follow-up: 21 months• Median PFS not reached

• Estimated 18-month PFS rate: 75%• No difference in PFS for pts

undergoing ASCT or not• Median OS not reached

• Estimated 18-month OS rate: 97%

• Most common AEs: • Sensory PN (80%), fatigue (64%),

constipation (61%), edema limb (45%), muscle pain (44%)

• Grade 3 PN: 7%, no grade 4• Overall rate of DVT/PE: 6%• No treatment-related mortality

Richardson et al. Blood 2010;116;679-686

Post-Transplant MaintenancePost-Transplant Maintenance

• Transplant settingTransplant setting 5/5 studies showed significant improvement in PFS5/5 studies showed significant improvement in PFS 2/5 studies showed significant improvement in OS2/5 studies showed significant improvement in OS

• Non-transplant settingNon-transplant setting 2/2 studies showed significant improvement in PFS2/2 studies showed significant improvement in PFS No significant improvement in OSNo significant improvement in OS

Thalidomide maintenance studies / SummaryThalidomide maintenance studies / Summary

ConsiderationsConsiderations

- Short survival following relapse in some studies

- Worse outcome in patients with poor cytogenetics

IFM 2005-02: IFM 2005-02: Lenalidomide as maintenance therapy Lenalidomide as maintenance therapy After ASCT for MMAfter ASCT for MM

Lenalidomide 10 -15 mg/day p.o., continuous dosing

until relapse

Lenalidomide 10 -15 mg/day p.o., continuous dosing

until relapse

Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line

Placebo until relapsePlacebo until relapse

Primary end-point : PFSSecondary end-points: CR rate, OS, feasibility of long-term lenalidomide.

Ongoing phase III randomized, placebo-controlled trial

ConsolidationLenalidomide 25 mg/day p.o., days 1-21 of

every 28 days for 2 months

ConsolidationLenalidomide 25 mg/day p.o., days 1-21 of

every 28 days for 2 months

RandomizeRandomize

IFM 2005-02 : PFS from randomization 0.0

00.2

50.5

00.7

51.0

0

0 6 12 18 24 30 36

Placebo Revlimid

p<10-7

P < 10-7

Lenalidomide

Placebo

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF

3 x VAD

MEL 200 + PBSCT

Depending on local

policy for patients PR MEL 200 + PBSCT

Thalidomide 50 mg/day for

2 years maintenance

Allogeneic TxAllogeneic Tx

HOVON 65 MM / GMMG-HD4HOVON 65 MM / GMMG-HD4

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

Depending on local policy for patients

PR MEL 200 + PBSCT

Bortezomib 1.3 mg/m2/2 weeks for 2 years maintenance

Accrual goal: 800 patients

IFM 2009/ DFCI TrialIFM 2009/ DFCI Trial

Major question: Can early SCT prolong EFS of at least 9 months? (1000 pts)

VRD x 3

SC collection

VRD x 5

Rev maintenance

(HDM + ASCT at relapse)

Mel 200 + ASCT

VRD x 2

Rev maintenance

Jean-Paul FermandPhilippe MoreauThierry Facon